Treatment of sterols



Patented Dec. 25, 1945 TREATMENT OF STEROLS Jacob Rosin, New York, N. Y.

No Drawing. Application November 4, 1944, Serial No. 562,040

1 Claim.

My invention relates to chromic steroid compounds, and method of formingor producingthe same. The present application is a continuation-in-partof my application Serial No. 498,589, filed August 13, 1943, and also acontinuationin-part of my application Serial No. 531,652, filed April18, 1944, which will mature into Patent No. 2,362,405 under date ofNovember 7, 1944-.

Steroid degradation products are widely used in the manufacture ofsynthetic sex hormones and other organic compounds having a great manypharmacological applications. The presently-known methods of producingthe synthetic sex hormones, while effective, are relatively uncertain,expensive, complicated and wasteful of raw materials. With the methodsof my invention, I am enabled to produce certain intermediate compounds,chromic steroids, from which the production of the ultimate degradationproducts, as one field of utility of my new products, may be achievedeasily, quickly, positively, at much less expense, much faster, and withgreater yields than heretofore. The new products, therefore, are ofgreat benefit and .utility and permit the manufacture of syntheticsexhormones much more eificiently than was possible prior to my isolationthereof by my new methods.

These new metalorganic compounds, the chromium oxychloride steroids,have never before been produced and isolated by any known method. Theirnature and composition will be discussed below.

From the metalorganic compounds formed by my new methods, I can producethe highly desirable ultimate degradation products simply and easily,this being but one field in which my new products may be used toadvantage.

The main object of my invention, therefore, is the formation of chromiumoxychloride steroids and method of producing the same, from steroidshaving an a iphatic side chain in the 17-position.

Another object of my invention is the formation of chromium oXychloridesteroids and method of producing the same from steroids having a sidechain in the 17-position and methyl groups in the and 13-positions suchchromium oxychloride steroids having at least one molecule of chromiumoxychloride bound to the side chain.

Another object of my invention is the formation of such chromiumoxychloride steroids in isolatable form.

Still another object of my invention is the provision of a method ofprecipitating in isolatable form such chromium oxychloride steroids fromsteroids having an aliphatic side chain at the 17-position.

Still another object of my invention is the Provision of amethod offorming chromium oxychloride steroids by reacting the steroids having aside chain at the 17-position with chromium oxychloride.

Still another object of my invention is the provision of a method ofprecipitating chromium oxychloride steroids by reaction of steroidshaving a side chain at the 17-position with chromium oxychloride.

Still another object of my invention is the provision of forming suchchromium oxychloride steroids by subjecting the steroids having a sidechain at the l'l-position to vapors of chromium oxychloride.

Depending on conditions to be detailed below, one or more molecules ofchromium oxychloride are permitted to enter into the steroid molecule,care being taken to prevent the decomposition of the chromiumoxychloride steroids during the reaction. Thus, in my process, there issubstantially a quantitative yield of chromium oXyChlO- ride steroids,plus unchanged raw material when the reactions are not completelycarried through. Once obtained, however, my metalorganic com pounds, thechromium oxychloride steroids, are protected against further reactionsince they are very resistant to chromium oxychloride, and the additionof more of the chromium oxychloride would merely result in a reactionbetween unchanged steroid material and the chromium oxychloride, and notbetween the chromium oxychloride and the already-formed chromiumoxychloride steroids. No oxidative degradation takes place during thisreaction in my process, which may be carried out either by directcombinatioi or by precipitation.

Once I have achieved the metalorganic compounds, the chromiumoxychloride steroids, I may then subject them to decomposition by wateror by other suitable non-oxidative agents. During this decomposition,the chromium salts are split off and simultaneously the degradation ofthe side chain is effected.- There is present, inthis particular use ofthe new products achieved by my process, no oxidative agency, and thedegradation is effected by the decomposition of every chromiumoxychloride sterol molecule which contains oxygen within itself. Everymolecule is subjected to degradation only as far or as long as its ownoxygen supply lasts, and there is no other or outside oxidative agent toattack the ultimate products and they are thereby protected.

This neld ot useoi my new product is described the chromium oxychloridesteroids to the ultimate degradation products desired. Also, I mayeliminate or substantially reduce the use of sol-.

vents in the interactions between the sterol-containing material and thehexavalent chromium.

As one example of my process, I may take a thousand (1,000) grams ofcholesterol dibromide and spread same in thin layers over the shelves ofa cabinet, covering a relatively large surface area. Wide-mouthed dishescontaining chromium oxychloride are disposed inside the cabinet onsupportsv above the shelves. The cabinet is then closed and sealedagainst the atmos-,- phere with parafiin, and kept sealed at roomtemperatures for twenty-four (24) hours. The cabinet may then be openedand the chromium oxychloride steroid removed, as by scraping, from theshelves. The material is dry, powdery and of light brown color. Itsweight is-equal to 200% to 210% of the cholesterol dibromide used. Nocalorific efiect was observed during the formation of this product. Thechromium oxychloride steroids achieved by this example may be furthertreated to yield progesterone.

As another example of my method, I may use cholesterol acetate dibromideas the starting material instead of the cholesterol dibromide, and treatsame as in the first example. The same dry, brown, powdery material willbe achieved, but it will yield upon decomposition and debrominationpregnenolo'ne acetate instead of progesterone.

As a third example of my method, I may ,dissolvesay 28.5 grams ofcholesterol acetate dibromide in 50 cc. of carbon tetrachloride,chloroform or any similar halogenated hydrocarbon. I thereafter add 10cc. (19.2 grams) of chromium oxychloride to the solution and agitate thesame under control to prevent overheating. Both the cholesterol acetatedlbromide and the chromium toincrease the dilutionotthe solution ofsteroids and chromium oxychloride, boiling under reflux becomesnecessary to achieve the reaction. This procedure is particularlysuitable for the introduction of a smaller number of chromiumoxychloride molecules into the steroid molecule.

. Thus, for instance, when a solution 01.5.9 grams of cholesterolacetate dibromide in 50 cc.oi carbon tetrachloride is mixed with asolution of 2 cc. of chromium oxychloridein 50 cc. of carbontetrachloride, no reaction takes place at room temperature. By heatingto 50 C. 'only a very slight reaction can be observed. Only by boilingfor a longer time under reflux can the reaction followed byprecipitation of a voluminous brown precipitate be achieved.

Within my method, other sterols as sitosterol.

stigmasterol, steroid genius and other steroid compounds having a sidechain may be used instead of cholesterol. p

The metalorganic products of my invention, the chromium oxychloridesteroids are found to be true reaction products, and not mere additioncompounds. This is proven by their decomposition by water. If they weremere addition compounds, the chromium oxychloride would immediatelyreact with water to form chromium trioxide and hydrochloric acid.Chromium trioxide, however, is absolutely unable to attack the steroidswhen only water isused, (water is a solvent for chromium trioxide butnot for the steroids), and if my products were addition compounds thedecomposition by water would yield chromium trioxide and .unchangedsteroid raw material. This does not happen, for (as recited in myco-pending application Serial No. 531,652), the decomposition of thechromium oxychloride steroids by water yields steroid degradationproducts and large quantities of trivalent chromium oxychloride are verysoluble in the halogenated hydrocarbon solvents, and a relatively smallamount of the solvent will suflice to support the desired reaction.After a while a brown precipitate will be formed. The solvent may beremoved easily as by filtration in a filter press, by distillation, ormerely permitted to evaporate. Preferably, it is collected for reuse infurther batches. The brown precipitate which weighs after drying 47.7grams will consist of the chromium oxychloride steroids, and thematerial may be used for the securement of degradation products asoutlined in my co-pending application Serial No. 531,652, issued asPatent No. 2,362,405, on November 7, 1944. When more solvent is usedsalts, thus proving that in my metalorganic compounds, the chromiumoxychloride is chemically attached to the steroid molecule, and does notreact as would mere physically attached chromiumoxychloride (thereaction between chromium oxychloride and water is immediate andstrongly exothermic). Therefore, my chromium oxychloride steroids arenot mere addition compounds but true reaction products.

As to the position of the chromium oxychloride in the steroid molecule,it is attached to the 17- side chain, since decomposition of thechromium oxychloride steroids affects only the side chain whereas thenucleus and the methyl groups in the 10- and 13-positions remainunaffected.

Having now described my invention, what I claim and desire to secure byLetters Patent is:

The method of treating sterols in order to form and isolate chromiumoxychloride sterols, which comprises reacting sterols with chromiumoxychloride in the presence of a non-polar solvent for both the sterolsand the chromium oxychloride, which solvent is resistant to chromiumoxychloride and inert to the chromium oxychloride

